Repression of IFN-γ Expression by Peroxisome Proliferator-Activated Receptor γ

Abstract

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors expressed in a wide variety of cells. Our studies and others have demonstrated that both human and murine T cells express PPARγ and that expression can be augmented over time in mitogen-activated splenocytes. PPARγ ligands decrease proliferation and IL-2 production, and induce apoptosis in both B and T cells. PPARγ ligands have also been shown to be anti-inflammatory in multiple models of inflammatory disease. In the following study, we demonstrate for the first time that PPARγ is expressed in both murine CD4 and CD8 cells and that PPARγ ligands directly decrease IFN-γ expression by murine and transformed T cell lines. Unexpectedly, GW9662, a PPARγ antagonist, increases lymphocyte IFN-γ expression. Transient transfection studies reveal that PPARγ ligands, in a PPARγ-dependent manner, potently repress an IFN-γ promoter construct. Repression localizes to the distal conserved sequence of the IFN-γ promoter. Our studies also demonstrate that PPARγ acts on the IFN-γ promoter by interfering with c-Jun activation. These studies suggest that many of the observed anti-inflammatory effects of PPARγ ligands may be related to direct inhibition of IFN-γ by PPARγ.

Peroxisome Proliferator-Activated Receptor γ Is Required for Regulatory CD4+ T Cell-Mediated Protection against Colitis

“…The overproduction of IFN-␥ by PPAR-␥ null CD4 ϩ T cells could result from defects in intrinsic effector CD4 ϩ T cell down-modulatory mechanisms and/or defects in extrinsic regulatory functions elicited by Treg. Cunard et al (27) reported that the reduction of IFN-␥ secretion by T cells treated with TZD was due to the inhibition of the IFN-␥ proximal promoter in Jurkat T cells transfected with a PPAR-␥ plasmid. These findings support the concept of intrinsic regulation of IFN-␥ production through PPAR-␥.…”

“…Previous experiments have shown that transfection of Jurkat T cells with a PPAR-␥ expression plasmid suppressed the IFN-␥ promoter (27). We tested whether the loss of PPAR-␥ would enhance IFN-␥ production by CD4 ϩ T cells exposed to Th1-polarizing conditions.…”

“…PPAR-␥ activation also regulates cytokine secretion by CD4 ϩ T cells (26). More specifically, PPAR-␥ activation by rosiglitazone decreased IFN-␥ production by splenocytes in vitro stimulated with PMA and ionomycin (27). Treatment of CD4 ϩ T cells with ciglitazone or 15-deoxy-PGJ2 triggered the physical association between PPAR-␥ and NFATc1, resulting in IL-4 promoter inhibition and decreased IL-4 production (28), and 13-hydroxyoctadecadienoic acid (13-HODE) a putative endogenously generated PPAR-␥ agonist, down-regulated IL-2 production by human peripheral blood T lymphocytes by reducing NFAT and NF-B binding to the IL-2 promoter (29).…”

Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer’s disease and decreases it in wild-type mice

“…The finding that thiazolidinediones are potent inhibitors of inflammation [3][4][5] has prompted several clinical trials testing the effects of thiazolidinediones in neurological diseases such as Alzheimer's disease and multiple sclerosis, in which inflammation contributes to pathogenesis [6]. The antiinflammatory properties of pioglitazone in the brain have also been shown in murine models of acute [7] and chronic [8] inflammation, when this thiazolidinedione was administered to the animals orally.…”

Peroxisome Proliferator-Activated Receptor γ Control of Dendritic Cell Function Contributes to Development of CD4+ T Cell Anergy

“…In monocytes and macrophages, PPAR␥ agonists inhibit the expression of a number of proinflammatory cytokines (8,9), and attenuate the oxidative burst (11). In T lymphocytes, PPAR␥ activation inhibits both Agspecific and nonspecific T cell proliferation and the production of several proinflammatory cytokines (12,14). Recently, it has been shown that PPAR␥ agonists prevent expression of IL-12 in murine DCs (15) and affect maturation of human monocyte-derived DCs as evidenced by altered surface expression levels of costimulatory molecules (16).…”